Psychoses are serious mental illnesses characterized by defective or lost contact with reality. Psychotic patients may suffer hallucinations and delusions as part of their disease. Psychoses exact a tremendous emotional and economic toll on patients, their families, and society as a whole. While the mechanisms underlying these diverse disease states are poorly understood, there are extensive efforts devoted to the discovery of therapies that may offer new hope for the treatment of psychotic patients.
Typical antipsychotic drugs, also called first generation or traditional antipsychotics, and atypical antipsychotic drugs (also called second generation antipsychotics) are indispensable in the pharmacological treatment of psychoses, such as schizophrenia and other neuropsychiatric conditions that are associated with psychotic states. Typical antipsychotic drugs include haloperidol, penfluridol, sulpiride, zuclopenthixol, flupenthixol, clotiapine and phenothiazines, such as chlorpromazine, prochlorperazine, flupenazine, trifluoperazine, perphenazine, levomepromazine and thioridazine, among others. The most common side effects associated with use of typical antipsychotics are extrapyramidal symptoms (EPS), particularly, dystonia (abnormal tonicity of the muscles), Parkinsonism and akathisia (motor restlessness). EPS may develop within hours to days of the implementation of treatment. Longer-term treatment is associated with development of the chronic, choreoathetotic movement disorder, tardive dyskinesia. The unpleasant side effects induced by antipsychotics often lead patients to stop using them.
Progress in the treatment of psychotic conditions has been achieved through the introduction of atypical antipsychotic agents (also known as second generation antipsychotics), which have a significantly decreased propensity to cause extrapyramidal side effects. Atypical antipsychotics include, but are not limited to: clozapine, risperidone, olanzapine, sertindole, quetiapine, and ziprasidone. While the side effect profile of these atypical antipsychotics is superior to that of typical agents with regard to EPS, treatment with these new drugs alone does not provide total relief to every psychotic patient. Improvement in the clinical efficacy of atypical antipsychotics is achieved, in certain patients, by combining these drugs with other antipsychotics, including typical antipsychotics, thereby exposing patients to onset or worsening of EPS.
The pathophysiology of EPS induced by antipsychotic drugs is still unclear. However, the most plausible explanation relates to the dopamine D2 receptor, the activity of which is mediated by two major classes of heterotrimeric G protein coupled receptors (GPCR). GPCR signaling is regulated by the regulators of G-protein signaling (RGS) proteins (Ingi et al., J Neurosci., 1998; 18:7178-88). RGS2 protein belongs to the B/R4 subfamily of RGS proteins (which also includes RGS1-5, RGS8, RGS13, RGS16 and RGS18). RGS mediate the activity of GTPase-accelerating proteins (GAP) and their interaction with G-alpha subunits (Hollinger and Hepler, Pharmacol Rev., 2002; 54:527-59). Among G protein coupled receptors whose signaling is reported to be influenced by RGS2 are the dopamine D1 receptor (Taymans et al., J Neurochem., 2003; 84:1118-27) and the 5-HT2A receptor (Ghavami et al., Cell Signal, 2004; 16:711-21).
SNPs in the RGS2 gene, including inter alia rs2746073 and rs4606, and haplotypes comprising same were shown to be associated with panic disorders (Leygraft et al., J. Neural Transm., Jun. 1, 2006; PMID: 16736243). The presence of a particular human D2 receptor gene allele was found to correlate with susceptibility to compulsive disorder, as disclosed in U.S. Pat. No. 5,500,343. However, nowhere in the background art is it taught or suggested that single nucleotide polymorphisms (SNPs) or haplotypes in RGS genes can indicate the susceptibility of a subject to develop EPS or to suffer from enhanced EPS during treatment with psychotic drugs.
An assay for predicting the potential ability of a drug to cause EPS in rats is disclosed in U.S. Pat. No. 4,086,350. The assay is based on calculating the ratio of the drug's ED50 (i.p.) for antagonism of amphetamine-induced rotation to the drug's ED50 (i.p.) for blockade of shock avoidance acquisition. This assay is suitable for application in laboratory animals.
A method for reversing or preventing extrapyramidal side effects in a human due to neuroleptic treatment is disclosed in U.S. Pat. No. 5,137,712. The method comprises concurrently administering to said human said neuroleptic and an effective amount of S-adenosyl-L-methionine or a physiologically acceptable salt thereof.
The aforementioned methods do not meet the requirement to determine susceptibility to EPS before initiation of the antipsychotic treatment. Such assessment of patients at risk for EPS is essential for optimization of antipsychotic treatment regimen.